microRNA regulation of NMNAT-mediated Neuroprotection against Peripheral Neuropathy and Chronic Pain

NMNAT 介导的针对周围神经病变和慢性疼痛的神经保护的 microRNA 调节

基本信息

批准号：
10879437
负责人：
Rong Grace Zhai
金额：
$ 6.19万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-16 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10879437
关键词：
Affect Afferent Neurons Award Behavioral Cancer Patient Chemotherapy-induced peripheral neuropathy Clinical Trials Computers Cultured Cells Data Science Development Doctor of Philosophy Dose Limiting Drosophila genus Drosophila inturned protein Environment Enzymes Essential Genes Family Functional disorder Genetic Genetic Transcription Glutamate-ammonia-ligase adenylyltransferase Goals Graduate Degree Grant Health Homeostasis Hypersensitivity Larva Maintenance Mammals Mediating Metabolism MicroRNAs Modeling Molecular Natural Compound Neurons Neuropathy Nicotinamide Mononucleotide Nociception Paclitaxel Pain Parents Pathway interactions Peripheral Nervous System Diseases Pharmacology Phase Physiological Population Protein Isoforms Proteins Puerto Rico RNA Splicing Regulation Research Research Project Grants Resort Role Sensory Symptoms Talents Testing Therapeutic Therapeutic Agents Training Transcriptional Regulation Variant Work arm candidate identification candidate selection career development chemotherapy chronic pain design effective therapy efficacy evaluation experience experimental study gain of function graduate student in vivo in vivo Model innovation innovative technologies loss of function mutation mRNA Expression mRNA Precursor mRNA Stability neural neuroprotection neurotoxic novel novel therapeutics opioid use pain model painful neuropathy parent project programs proteostasis recreational drug use recruit resilience response screening side effect success therapeutic miRNA tool

项目摘要

PROJECT SUMMARY Peripheral neuropathy and neuropathy pain can be caused by a myriad of genetic and environment factors as well as therapeutic or recreational drug use. In particular, chemotherapy-induced peripheral neuropathy (CIPN) is the major dose-limiting neurotoxic side effect of standard chemotherapy regiments. Over 68% of cancer patients experience neuropathic symptoms after chemotherapy, and that contributes to a significant percent of the population that suffer from chronic pain and have to resort to opioid use. Currently there are no effective treatments available, largely due to a lack of understanding of the in vivo mechanisms of CIPN and related peripheral neuropathy. Recently, we have optimized a model of peripheral neuropathy using Drosophila larvae that recapitulates salient behavioral, physiological, and cellular aspects of chemotherapy- induced sensory dysfunction. Our preliminary work using this model has uncovered a new mechanism underlying peripheral neuropathy and identified a neuroprotective protein NMNAT with promising potential for mitigating neuropathic pain. The ultimate goal of our research is to uncover the endogenous mechanisms underlying peripheral neuropathy and to identify neuroprotective mechanisms and potential targets that facilitate the development of new therapeutic agents against CIPN and related neuropathic pain. Extensive mechanistic studies from our lab and others have found NMNAT proteins in Drosophila and mammals to be among the most robust and versatile neuroprotective factors, and a positive correlation between NMNAT expression levels and the neuronal self-protective capacity. Excitingly, from a compound screen, several natural compounds were identified to upregulate NMNAT transcription, and we have collected intriguing preliminary results suggesting that the expression of NMNAT is regulated by microRNAs. We hypothesize that regulation of NMNAT RNA expression by natural compounds and microRNAs at the steps of transcription, pre- mRNA splicing, and mRNA stability allows rapid and dynamic shifting between NMNAT mediated NAD+ metabolism and neuronal resilience and confers protection in sensory neurons against peripheral neuropathy. In this application we outline experiments to (1) identify microRNAs that regulate nociceptive hypersensitivity, (2) identify and characterize the molecular pharmacology of natural compounds in regulating NMNAT expression, and (3) modulate NMNAT transcriptional regulation to enhance neuroprotection against peripheral neuropathy. The objectives for the supplement application are to expand our testing portfolio to include 12 microRNAs and 24 natural compounds. With the recruitment of a full graduate student effort, we will be able to expand our candidate screening portfolio by > 80% and will significantly increase the likelihood of success in identifying candidates with high neuroprotective potential. In addition to the scientific goals, this diversity supplement will also support the PhD training in novel natural compound discovery for pain and fulfill the career development goals of Ms. Natalie Ortiz Vega in the field of natural compound pharmacology.

项目概要周围神经病变和神经病变疼痛可由多种遗传和环境引起因素以及治疗性或娱乐性药物的使用。特别是化疗引起的外周血神经病变（CIPN）是标准化疗方案的主要剂量限制性神经毒性副作用。超过 68% 的癌症患者在化疗后会出现神经性症状，这导致很大一部分人口患有慢性疼痛，不得不求助于阿片类药物。目前有目前尚无有效的治疗方法，很大程度上是由于对 CIPN 的体内机制缺乏了解以及相关的周围神经病变。最近，我们利用以下方法优化了周围神经病变模型果蝇幼虫概括了化疗的显着行为、生理和细胞方面—— 诱发感觉障碍。我们使用该模型的初步工作发现了一种新的机制周围神经病变并鉴定出一种具有缓解周围神经病变潜力的神经保护蛋白 NMNAT 神经性疼痛。我们研究的最终目标是揭示潜在的内源机制周围神经病变并确定促进周围神经病变的神经保护机制和潜在目标开发针对 CIPN 和相关神经性疼痛的新治疗剂。我们的实验室和其他实验室进行了广泛的机制研究，发现果蝇和哺乳动物是最强大和最通用的神经保护因素之一，并且两者之间呈正相关 NMNAT 表达水平与神经元自我保护能力。令人兴奋的是，从复合屏幕上，有几个天然化合物被鉴定出可以上调 NMNAT 转录，我们收集了有趣的信息初步结果表明NMNAT的表达受到microRNA的调节。我们假设天然化合物和 microRNA 在转录、预转录步骤中对 NMNAT RNA 表达的调节 mRNA 剪接和 mRNA 稳定性允许 NMNAT 介导的 NAD+ 之间快速动态转换代谢和神经元弹性，并保护感觉神经元免受周围神经病变的影响。在此应用中，我们概述了以下实验：(1) 识别调节伤害性超敏反应的 microRNA， (2) 鉴定和表征天然化合物调节 NMNAT 的分子药理学表达，以及（3）调节 NMNAT 转录调控以增强针对外周神经的神经保护神经病。补充申请的目标是扩大我们的测试组合以包括 12 microRNA 和 24 种天然化合物。通过招募全部研究生的努力，我们将能够将我们的候选人筛选组合扩大超过 80%，并将显着增加成功的可能性识别具有高神经保护潜力的候选人。除了科学目标之外，这种多样性补充品还将支持新型天然化合物发现治疗疼痛的博士培训并实现职业生涯 Natalie Ortiz Vega女士在天然化合物药理学领域的发展目标。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

MicroRNA-Mediated Obstruction of Stem-loop Alternative Splicing (MIMOSAS): a global mechanism for the regulation of alternative splicing.

MicroRNA 介导的干环选择性剪接阻碍 (MIMOSAS)：一种调节选择性剪接的全球机制。

DOI：
10.21203/rs.3.rs-2977025/v1
发表时间：
2023
期刊：
Research square
影响因子：
0
作者：
Zhai,Rong;Ruan,Kai;Perez,GermanFarinas;Kubat,Miroslav;Liu,Jiaqi;Hofacker,Ivo;Wuchty,Stefan
通讯作者：
Wuchty,Stefan